Effect of intermittent exposure to 3% C0 respiration, …i !! / ' e? Undersea Biomedicat Research,...

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Undersea Biomedicat Research, Submarine Supplement 1979

TI b CAP«

Effect of intermittent exposure to 3% C02 on respiration, acid-base balance, and

calcium-phosphorus metabolism

K. E. SCHAEFER, C. R. CAREY, J. H. DOUGHERTY, JR., C. MORGAN, and A. A. MESSIER

Naval Submarine Medical Research Laboratory. Naval Submarine Base, Grown, CT 06340

Schaefer, K. E., C. R. Carey, J. H. Dougherty, Jr., C. Morgan, and A. A. Messier. 1979. Effect of intermittent exposure to 3% CQ2 on respiration, acid-base balance, and calcium-phosphorus metabolism. Undersea Biomed. Res. Sub. Supp.: S115-S134.—One subject was exposed for six days to increasing levels of COj, rising at a constant rate from 0.03 to 3.0% CO, within a 15-h period followed by 9 h of air breathing. To assess acid-base parameters, arterialized capillary blood was taken from a finger twice daily (at 8 a.m. and 11 p.m.) at times corresponding to the beginning and end of the intermittent exposure to COj, Venous blood samples were obtained on alternate days at the same times. Urine specimens were collected twice daily. The subject was on a liquid diet. Resting respiratory minute volume (VE), oxygen consumption (Voj), carbon dioxide excretion (VcQz), alveolar carbon dioxide and oxygen tension (PACOI) and (PAQ,) were measured twice daily. PACO, and PAO, were also determined at the end of breath-holding twice daily; CO2 tolerance tests and lung function tests were also carried out. In contrast to the effects of chronic exposure to 3% COa, the COj tolerance tests showed an increased sensitivity (increase of slope) and breath-holding PACQ, did not change, indicating that acclimatization to COt did not develop. The ventilatory response to COj was not sufficient to prevent COi accumulation in the body; this accumulation was eliminated during the nightly air-breathing periods on the fourth and fifth days, indicated by higher values of Pace and PACO,. The known renal response to hypercapnia, consisting of an increased excretion of titratable acidity, ammonia, and hydrogen ion excretion, occurred but was interrupted after the first day and was triggered again on the fourth and fifth days when accumulated CO, was released from body COj stores. The second renal response was associated with a marked calcium excretion, which suggests that bone COj stores were involved.

co2 respiration breath-holding

renal function calcium metabolism

Several studies have been carried out on the effects of prolonged exposure to increased carbon dioxide concentrations on respiration and acid-base parameters in man (Schaefer 1949;

S115

A- S116 SCHAEFER ET AL.

Sullivan and Dorman 1955; Chapin, Otis, and Rahn 1956; Schaefer 1961; Schaefer, Hastings, Carey, and Nichols 1963; Schaefer, Nichols, and Carey 1964; Schwartz, Bracke«, and Cohen 1965; van Ypersele De Strihou, Brasseur, and DeConincok 1966; Glatte, Motsay, and Welch 1967£Brackett, Wingo, Muren, and Salano 1969; Clark, Sinclair, and Welch 1971). There are, however, no comparable investigations of the effect on man of intermittent exposure to C02. This problem is of practical significance for snorkel-type submarines, which are submerged during the day and therefore have a rising C02 concentration in the atmosphere and which ventilate with air during snorkel operation at night. These submarine conditions were simu- lated in the present study. The purpose of this investigation was to determine whether body stores are saturated with C02 during repeated exposure to COz concentrations increasing from 0.03% to a final value of 3.00% C02 at the end of a 15-h exposure and whether the respiratory acidosis induced by intermittent exposure to C02 becomes compensated after 5 days, which would correspond to findings for chronic exposure to 3% C02 (Schaefer 1949).

MATERIALS AND METHODS

The experimental design consisted of a systematic study of respiration, acid-base balance, calcium metabolism, and visual performance. This required a great number of measurements during the day. Under these conditions the study was limited to one subject, a healthy 23- year-old medical student, thoroughly experienced in all tests performed.

The study was conducted in a large pressure altitude chamber in which constant tempera- ture and humidity could be maintained. Carbon dioxide was admitted from cylinders outside the chamber at a constant rate, resulting in a linear increase of C02 from 0.03 to 3% within a period of 15 h. At the end of the I5-h period (11 p.m.), the chamber was opened and ventilated with a fan. During the subsequent 9 h of air breathing, the subject slept. There were three control days prior to intermittent exposure to C02 for six days, followed by three days of recovery on air. The subject's vital data were: age, 23 years; height, 5 ft 7 in.; weight, 147 lbs.

Respiratory studies

Resting respiratory minute volume CV"E), oxygen consumption (fo^, carbon dioxide excretion (^coj), alveolar carbon dioxide and oxygen tensions (PACO, and PAO4), were measured twice daily, between 8-9 a.m. and 10:30-11p.m. End-tidal gas samples were collected during a 10-min period with a Rahn sampler and mixed expired air was collected in Douglas bags. Carbon dioxide and 02 concentrations were analyzed continuously with a Beckman LB-1 infrared C02 meter and a Servomax 02 meter. The obtained values were averaged and are reported as alveolar gas tensions. Mixed expired gas was collected in a Douglas bag for the last six minutes of the 10-min test period. Volume measurements were made with a dry gas meter. Oxygen uptake and C02 excretion were calculated by adding values of expired and alveolar samples. The respiratory rate was determined with a Yellow Springs thermistor inserted at the side of the mouthpiece.

Carbon dioxide tolerance tests, consisting of a 10-min inhalation of 5% C02 in 21% 02, were carried out on six occasions twice daily, after the measurement of resting ventilation. VE/PACO,

values obtained at conditions of rest and breathing 5% COj were plotted and the actual slope measured. Breath-holding time and PACO, and PAO2 at the breath-hold breaking point were measured every morning between 8-9 a.m. and every evening between 10 and II p.m.

INTERMITTENT EXPOSURE TO CO* S117

Moreover, (he time at which diaphragmatic movements occurred prior to the end of breath- holding time was also measured. ■■•"•"••'.' :-•.:.;

—Lung voluiQ£S_and flow rates were determined by the maxima! inspiratory-expiratory velocity-volume technique. A Wedge spirometer (Model 370 by Med-Science Electronics), a Tektronic type 502A dual-beam oscilloscope, and a Tektronic oscilloscope camera Model C-12 with a Polaroid film holder were used.

Vital capacity, tidal volume, inspiratory capacity, expiratory reserve volume, maximal expiratory flow rate (MEFR) and maximal inspiratory flow rate (MIFR) were calculated from the photograph.

The subject was trained before experiments commenced. The effort-dependent characteris- tics of these tests were explained and the importance of a maximal effort was stressed. The flow-volume loops were run in duplicate. If one of the two loops appeared by quick visual inspection to be much smaller in terms of flow or volume, it was discarded and a third determination made. The larger of the two vital capacity values was used; the inspiratory capacity and expiratory reserve volume data were taken from this same photograph. The larger of the two MEFR and MIFR values was chosen, regardless of which determination it occurred in.

Blood studies

To assess the acid-base parameters, capillary blood samples were taken from the finger twice daily, at 8 a.m. and 11 p.m. The capillary blood was arterialized by heating the finger to approximately 45°C for five minutes. The free-flowing arterialized blood was collected anaerobically in heparinized capillary tubes and sealed with clay. These samples were placed on ice and analyzed within 30 min for pH, Pco2, and Po2 on the Instrumentation Laboratory ultramicro blood gas analyzer, Model 113. Duplicate determinations were made. The validity of equating pH and blood gas tensions of arterialized capillary blood with those of arterial blood has been repeatedly demonstrated by, among others, Gambino (1959).

Venous blood samples were taken twice daily from the antecubital vein at less frequent intervals (every second day) and also analyzed for pH, Pco2, and Po2. Moreover, determinations of serum Na, K, and Cl were carried out. Blood lactate and pyruvate were also measured. Unfortunately, serum samples scheduled for Ca, Mg, and P determinations were affected during transport and could not be used.

Urine studies

The collection periods of urine corresponded to the experimental periods of air breathing (11 p.m.-8 a.m.) and C02 breathing (8 a.m.-11 p.m.). Urine specimens were collected twice daily at 8 a.m. and 11 p.m. in bottles containing thymol and a layer of mineral oil. Urine volume, pH, C02, Ca, Mg, and phosphate were determined, in addition to organic acids, ammonia, and titratable acidity. Net hydrogen ion excretion was calculated (ammonia - titratable acidity - HCO3). Urinary hydroxysteroids were determined with a modified Porter-Silber procedure (Bray's Clinical Laboratory Methods 1962). Urinary calcium, magnesium, and phosphorus, hydroxyproline and sulfur as well as feces content of calcium, phosphorus, and magnesium were determined in the laboratory of Dr. Bernstein at the Harvard School of Public Health. Throughout the experiment, the subject was on a liquid diet, with a constant liquid intake of 2,25 liters/day and 2795 calories/day. The diet contained 281 mg calcium and 1000 mg phosphorus per day throughout the entire experimental period. An additional 423 mg of calcium

S118 SCHAEFER ET AL.

was given in the form of calcium gluconate. Chromium sesquioxide was used as fecal mark. Sodium and potassium were analyzed by an internal standard (lithium) flame photometer

_Ca|c.um and magnes.um were determined by atomic absorption. Phosphorus was determine according to thelflethod of Fisk"eahd Subbardw7T925). ~ ""determined

RESULTS

Respiration

The effect of intermittent exposure to CO, on pulmonary ventilation and alveolar gas ten sions «shown «, F,g I and Table 1. Respiratory minute volume increased to twice the res „e

vent.lation on a,r at the end of the 15-h exposure to rising C02 concentrations reaching1% CO a the time the measurement was made. Alveolar C02 tension rose from 40.7 mmHg (avenS of 3 da.ly measurements at 11 p.m.) to 42.4 mmHg (average of 6 daily measurements a 11 pT

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c°2 fxp°su/e)- ™viveoiar °* tension increased fr°m «*-7 21 ur8 mmHg. All the values obtained after 9 h of air breathing remained at control levels with th

excePt.on of the alveolar CO, tension, which rose on the fourth and fifth days, reaching peak

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—INTERMITTENT EXPOSURE TO • 3% COt

MORNING NICHT X X CO, EXPOSED

—RECOVERY AIR PCOt (alveolar)

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ö H O

i ' 8 ' 4 TWE IN DAYS

POi (alveolar)

V» BTPS

n n

Atmospheric COt Level

Fig. I. Effect of intermittent exposure to 3% COi on alveolar PcOj and Po2 and respiratory minute volume (BTPS). Daily rise of ambient COs from zero to 3% CQj over a I5-h period is indicated in lower panel.

INTERMITTENT EXPOSURE TO CO, S119

TABLE 1 EFFECTS OF INTERMITTENT EXPOSURE TO 3% C02

' VE(BTPS)," liter/min mmHg ml/min ml/min

"

Condition PA«,,

mmHg R

Control, Mean 5.68 40.7 101.0 186.5 236.0 0.79 8 a.m.

n 2 2 2 2 2 2

Control, 11 p.m.

Mean SEM n

6.22 0.27 3

40.7 1.2 3

100.7 1.2 3

205.7 6.2 3

252.7 8.2 3

0.81 0.01 3

Experimental: 9 h on air at 8 a.m.

Mean SEM n

5.99 0.17 6

40.4 0.9 6

101.8 1.4 6

189.2 3.0 6

233.8 10.9 6

0.86 0.04 6

Exposure: 15 h on COj (3%C02) 11 p.m.

Mean SEM n

12.35** 0.70 6

42.4 0.4 6

114.8** 1.5 6

228.2** 7.8 6

248.5 11.1 6

0.92* 0.02 6

Recovery on air, 8 a.m.

Mean SEM

n

5.79 0.47 3

39.0 0.2 3

100.8 1.2 3

183.3 12.0

3

236.3 12.2 3

0.78 0.02 3

Recovery on air, 11 p.m.

Mean SEM n

6.59 0.70 3

38.8 1.4 3

105.0 0.7 3

♦Statistically different from control levels; **significant difference between data obtained after 9 h on air (8 a.m.) and 15 h on COj at 11 p.m. at the 5% level or better.

even higher than the corresponding value on C02 breathing. This indicates that the 9-h period of air breathing was not sufficient after three days to eliminate the previously accumulated C02.

Data on oxygen consumption, C02 excretion, and respiratory exchange ratio are also presented in Table 1 and daily changes in these measures in Fig. 3. Carbon dioxide excretion was consistently elevated during C02 breathing, except on Day 6. The oxygen consumption during air breathing declined from 250 to 180 ml on Day 5, a condition which led to an increase of the respiratory exchange ratio during the fourth and fifth days that corresponded to the rise in alveolar C02 tension. The subsequent return of the respiratory exchange ratio to near normal values on the sixth day of intermittent C02 exposure was paralleled by the fall in alveolar C02

tension and a return of both VcOj and 'v'Oj to control values. This suggests that the previously accumulated C02 was released from the body C02 stores during the two air-breathing periods that comprised a total of 18 h.

The average ventilatory response to inhalation of 5% C02 increased during the six-day period of intermittent exposure to 3% C02, as shown in Table 2. PACO* tended to decrease and PA0» to rise. The slope of C02 tolerance curves increased during the intermittent exposure to COj and during the recovery period on air.

The alveolar Pco2 and Po2 values obtained at the end of breath-holding, together with breath-holding times, are depicted in Fig. 2. The PACO* values measured at the end of 15 h of rising ambient C02 did not rise above control values obtained under air at 10-11 p.m., indicating that acclimatization to C02 did not occur. PACO, measured at the end of breath-


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Fig. 2. PACO, and PA0, values at end of breath-holding and breath-holding time.

holding after 9 h on air did increase from the third to the fifth day, reaching a value higher than the corresponding PACO* values after C02 exposure on the fifth day. This is in agreement with the findings obtained during resting ventilation (Fig. 1).

A summary of the data on breath-holding is presented in Table 3. Breath-holding time and latent time of onset of diaphragmatic movements significantly decreased during intermittent exposure to C02. As a consequence, PA02 increased; PACO, remained unchanged.

Intermittent exposure to 3% C02 had effects on lung functions (Table 4). Maximum volun- tary ventilation (MVV) showed a consistent trend to rise during the experiment. Vital capacity tended to decrease at the end of the 15-h period of C02 exposure and also in the morning after a 9-h period of air breathing. The same was true for the expiratory reserve volume, while inspiratory capacity was unaffected during the exposure period. The maximum expiratory flow rates (MEFR) did decrease during the experimental period and they remained below control levels during the recovery period on air, in contrast to the maximal inspiratory flow rates (MIFR), which did not change.

Acid-base status

The acid-base status of the blood (arterialized capillary blood) is exhibited in Fig. 4 and Table 5. Both hydrogen ion concentrations and arterial C02 tension showed a small but

INTERMITTENT EXPOSURE TO C02 S121

TABLE 2 EFFECTS OF INTERMITTENT EXPOSURE TO 5% C02 FOR SIX DAYS

^E (BTPS), liter/m

Slope of Cd

Conditions P<VO:ii mmHg

PAO,, mmHg

tolerance curves

Control Mean Range «

19.58 (18.9-20.3)

2

49.5 (49.0-50.0)

2

132.7 (131.7-133.7)

2

0.365 (0.31-0.42)

2

Intermittent C02 period of 6 days

Recovery on air

Mean SE n Mean SE n

24.37* (1.64)

6 21.62 (0.80)

4

47.04 <0.59)

6 45.06 (0.33)

4

136.7 (0.75)

6

135.1 (1.77)

4

0.493* (0.031)

6

0.520* (0.042)

4

♦Significantly different from controls at the 5% level or better.

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CONTROL AIR—*

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INTERMITTENT EXPOSURE TO • 3%C02

• *—RECOVERY AIR*

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@ x x CO« EXPOSED

Fig. 3. Effect of intermittent exposure to 3% C02 on ^co2, Vo2 and respiratory quotient (RQ).


TABLE 3 EFFECTS OF INTERMITTENT EXPOSURE TO C0t FOR SIX DAVS

Breath-holding Time,

s

Diaphragmatic Movements,

s

—.

Condition PAC -<h > mmHg

PA,,,, mmHg

Control, 8 a.m.

Mean SEM n

154.8 7.8 3

88 4.0 3

55.3 1.9 3

46.2 5.6 3

Control, 11 p.m.

167.7 3.5 3

92.5 2.5 3

58.2 0.4 3

41.8 1.9 3

Intermittent Exposure, 9 h on air,

163.4 3.5 6

88.5 7.7 6

54.3 0.7 6

47.5 2.1 6

8 a.m. Intermittent

Exposure, 15honC02, 11 p.m.

Recovery on Air, 8 a.m.

141.4* 7.2 6

183.5* 3.7 3

68.7* 5.9 6

110.3* 2.7 3

57.3 0.6 6

53.7 1.1 3

64.6* 4.0 6

47.1 2.3 3

Recovery on Air, 11 p.m.

164.7 12.2 3

101.0 7.5 3

56.0 1.0 3

48.6 4.2

•Significantly different from controls at the 5% level or better.

consistent elevation during C02 breathing, amounting to 1-2 nM and 1-2 mmHg C02. The values obtained during air breathing remained at control levels, with the exception of

the fourth and fifth days, when they rose to higher values than those measured during C02

breathing. The blood bicarbonate values did not change significantly under both air breathing and C02 exposure. Data obtained from venous blood (Fig. 5 and Table 5) showed similar changes in hydrogen ion concentrations and C02 tension during C02 exposure. Oxygen tensions in both arterial and venous blood increased during C02 breathing (Fig. 6), which confirms the findings on alveolar oxygen tensions.

Blood lactate and pyruvate and L/P ratio were not affected by intermittent exposure to C02, The 17-hydroxysteroid excretion in the urine exhibited large diurnal variations that were not influenced by intermittent exposure to C02.

To delineate the effects of CO* breathing (8 a.m. to 11 p.m.) from air breathing (11 p.m. to 8 a.m.), data on urinary excretion are presented for the corresponding experimental periods; data on 24-h urine excretion wouid have obscured the effects of C02 breathing.

The responses of the renal functions primarily involved in acid-base regulations are shown in Fig. 7. There was an immediate response to C02 breathing on the first day, shown by an increase in urine volume and excretion of organic acids, titratable acidity, ammonia, and net acid excretion, followed by a decline in these parameters during the next two days. However, during the fourth and fifth days, which were marked by an increased C02 excretion and acid load during the air-breathing period, there was a marked rise in urine volume, organic acids,

INTERMITTENT EXPOSURE TO C02 S123

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TABLE 4 EFFECTS OF INTERMITTENT EXPOSURE TO 3% CO? ON LUNG FUNCTIONS

— VC, liters liters

ERV, liters

—MEFR, liter/s

MIFR— liter/s

MVV : ' Condition Iiter/min

» (

Control, 8 a.m.

Mean SEM n

5,83 0.08 3

3.61 0.01 3

2.22 0.08 3

14.05 0.15 3

12.66 0.28 3

198 16 3

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Control, 11 p.m.

Mean SEM n

5.87 0.07 3

3.95 0.10 3

1.93 0.03 3

13.51 0.34 3

12.18 0.54 3

210 12

3

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Experimental on air, 8 a.m.

Mean SEM n

5.62 0.05 6

3.68 0.04 6

1.94* 0.04 6

12.90* 0.27 6

12.74 0.15 6

225 3 6

t i

Experimental on 3% CQj, 11 p.m.

Mean SEM n

5.73 0.03 6

3.97 0.07 6

1.77 0.07 6

12.94* 0.16 6

12.82 0.20 6

225 5 6

1 1

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Recovery, 8 a.m.

Mean SEM

n

5.67 0.06 3

3.91* 0.07 3

1.76* 0.01 3

12.56* 0.11 3

12.55 0.27 3

244 3 3

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Recovery, 11 p.m.

Mean SEM n

5.80 0.01 3

3.97 0.14 3

1.82 0.01 3

12.45* 0.48 3

12.96 0.23 3

245* 2 3

'Significant difference from control levels at the 5% confidence level.

titratable acidity, ammonia, net acid, and hydrogen ion excretion. During the second day of recovery, an opposite trend could be noted,which was characterized by a decreased excretion of ammonia and titratable acidity and a reduction in hydrogen ion excretion commensurate with a large increase in bicarbonate elimination.

Figure 8 exhibits the urinary excretion of chloride, sodium, potassium and bicarbonate. These parameters showed a response pattern similar to that of ammonia and acid excretion: an initial increase on the first day of exposure, a subsequent decline during the second and third days, followed by a marked increase during the fourth and fifth days. On the sixth day of exposure there was again a fall to the level of excretion present on the second and third days. During the first and third days of the recovery period a pronounced increase in urinary excretion of chloride, sodium, and potassium occurred, in contrast to bicarbonate excretion, which reached a peak during the second day of recovery on air.

Urinary excretion of calcium, magnesium, phosphate, hydroxyproline, and sulfur is shown in Fig. 9. Calcium excretion did not show an immediate response the first day of C08 exposure. However, it increased between the second to fifth days, coinciding with the filling of C02

stores during the second and third days and their subsequent emptying on the fourth and fifth days. During the sixth day of exposure and during the recovery period on air, urine calcium excretion returned to control values. Magnesium excretion fell immediately during the first 15 h of exposure to CC^, and increased during the subsequent 9 h of air breathing during the night. The second day there was a greatly reduced magnesium excretion both during the C02- and air-breathing periods. During the subsequent exposure and recovery periods, magnesium excretion remained below control levels. Phosphate, hydroxyproline, and sulfur excretion in


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INTERMITTENT C0t EXPOSURE ■ ■ RECOVERY -

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Fig. 4. Effect of intermittent exposure to 3% C02 on hydrogen ton concentration, C08 tension, and bicarbonate levels of arterialized capillary blood. Solid line, values obtained at 8 a.m. on air; dotted line, values obtained at 11 p.m. at end of C02 exposure.

the urine did not change during intermittent exposure to 3% C02. Data on calcium, phosphorus, and magnesium excretion are presented in Table 6. During C02 exposure, urinary calcium excretion increased; fecal calcium excretion remained practically the same. Phos- phate and magnesium excretion in urine and feces decreased during intermittent exposure to 3% COj.

DISCUSSION

The experimental design of this study of intermittent exposure to C02 required the schedul- ing of measurements at 8 a.m., prior to eating, and 11 p.m., three hours after supper. Diurnal variations of physiological functions therefore influenced the measurements, and comparisons have to be made of corresponding time periods.


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Fig, 5. Effect of intermittent exposure to 3% COs on hydrogen ion concentration, C02 tension, and bicarbonate level of venous btood. Solid line, values obtained at 8 a.m. on air; dotted line, values obtained at 11 p.m. at end of C02 exposure.

Moreover, the alternating periods of air breathing and C02 breathing during intermittent exposure both exhibited C02 effects. Carbon dioxide, which accumulated during the previous 15-h period of C02 breathing, was not entirely eliminated during the subsequent 9-h period of air breathing. This is indicated by three findings: alveolar Pco2 and arterial Pco4 under resting conditions, as well as PAC0, at the breath-holding breaking point, rose at the end of the air-breathing period on Day 5 to values higher than corresponding values at the end of the C02

breathing period. Enough of the previously accumulated COä during the air-breathing period on Day 5 was eliminated to return alveolar and arterial Pco2 on Day 6 to the levels observed on Days 1 and 2 of the intermittent exposure.

In the recovery period on air, alveolar and blood carbon dioxide quickly returned to control values after 8 h of air breathing and remained at this level, but the main carbon dioxide elimination occurred on the second day of recovery, indicated by a large excretion of urine bicarbonate. This suggested that the metabolic effects of COa were still present at the time of the recovery period when alveolar and blood C02 tensions were essentially normal.

At the end of the 15-h exposure to a C02 concentration rising from 0-3% CC^, average respiratory minute volume had increased to twice the control value on air. A marked increase


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Fig. 6. Effect of intermittent exposure to CO» on Po» of arterialized capillary blood and venous blood. Solid line, values obtained at 8 a.m. on air; dotted line, values obtained at 11 p.m. at end of CO» exposure.

in ventilation tends to minimize changes in alveolar Pco2 and raise alveolar Pos. PACOJ increased by 1.7 mmHg and PA<,2 by 14.1 mmHg. These findings are in line with calculations Rahn and Fenn (1955) made for inhalation of 2.8% C02 in air: + 3 mmHg PAeo, and + 16 mmHg PAO*. The average arterial-alveolar difference in Pco2 ranged between 0.5 and 0.7 mmHg during the air-breathing period of intermittent exposure and during the recovery periods on air. These are reasonable values. However, the arterial-alveolar Pco2gradients of 3.5 and 4.1 observed during the control periods were too high, probably because PAC02 values measured at the beginning of the experiment were too low. During intermittent exposure to C02, A{a - A)Pco2 rose from 0.6 to 1.2 mmHg while A(A - a) Po, increased from 15.5 to 22 mmHg. The changes in (A-aJPo, are similar to those during exposure to 1.5% COj, when they increased from 10.6 to 25 mmHg (Schaefer et al. 1963). A significant increase in both arterial- alveolar Pco2 and Po2 gradients has been interpreted as indicating an increase in non-perfused and nonventilated alveoli (Schaefer et al. 1963). Trends in this direction were also seen in the present experiment involving intermittent exposure to C02.

The effects on respiration of intermittent exposure to 3% COä in this study differ in several ways from the well-known effects of chronic exposure to 3% C02. An increased ventilatory response to C02 and an increased slope in the C02 response curve during intermittent exposure to 3% COj are responses opposite to the depression of ventilatory response and decrease in slope observed in chronic exposure to 3% COt (Schaefer 1949; Clark et al. 1971).


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PACO, values at the end of breath-holding did not increase during intermittent exposure to 3% C0j (Fig. 2, Table 3), in contrast to the findings obtained by Chapin et al. (1956) in two subjects during chronic exposure to 3% CO«. After 13 h on 3% C02) breath-holding PAC03

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The average breath-holding time at the end of the 15-h exposure to rising C02 concentration reaching 3% C02 was reduced by 27 s, compared to corresponding evening control values at 11 p.m. while breathing air. As a result, the PADa values were increased. The fact that PACO, did not change during intermittent exposure to C02 while breath-holding time was shortened suggests an increased sensitivity to C02, which corresponds with the finding of an increased slope in the C02 response curve.

A transient increase and decrease in body C02 stores within a 5-day period resulted in normal values for alveolar C02 tensions and pulmonary gas exchange on the sixth day of intermittent exposure. It is therefore not possible to speak of compensation of a respiratory acidosis.

One similarity between intermittent and chronic exposure to 3% C02 was interesting: the same period of five days was required to return to control levels in the first case and to develop a compensation of the respiratory acidosis in the second case.

The steady rise in MVV is probably a training effect. The small increase in IC and corresponding decrease in ERV during the air-breathing periods of intermittent exposure to C02

and during the recovery period after C02 exposure appears to reflect a fall in FRC. In view of


Fig. 9. Effect of intermittent exposure to 3% C02 on urinary excretion of calcium, magnesium, phosphate, hydroxyproline, and sulfur, in mEq per time period. Black bars, 15-h excretion from 8 a.m.-11 p.m. breathing CO*; stipled bars, 9-h excretion during night from 11 p.m. to 8 a.m. breathing air.

these findings it is difficult to interpret the decrease in MEFR of approximately 1 liter/s during both experimental periods and during the recovery period as an increase in airway resistance.

The results of blood gas and pH measurements are in full agreement with the data on alveolar carbon dioxide tensions that show an increase in hydrogen ion concentration and Pcos in capillary blood during the air-breathing periods of the fourth and fifth days, which indicate a C02 accumulation in the organism. The two defense mechanisms against accumulation of C02, increased lung ventilation and renal regulation, were apparently not operating efficiently enough to prevent this accumulation. There was an immediate rena! response to C02 exposure during the first day that consisted of increased excretion of organic acids, titratable acidity, and ammonia, and which returned to control levels during the subsequent second and third days of 15 h of exposure to a rising ambient C02 level. This means that the renal response to the COa -induced acidosis was not maintained, as is the case with chronic C02 exposure to higher C02 concentrations (Schwartz et al. 1965). Based on the available data, it is not possible to explain why the renal response was turned off on Day 2. At the fourth and fifth days, however, when the C02 stores of the body began to empty (causing a higher alveolar and blood C02 tension at the end of a 9-h air-breathing period), a second and much more pronounced rena! response occurred, shown by the large increase in excretion of titrat-


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SI32 SCHAEFER ET AL.

able acidity, organic acids, ammonia, and net acid. At this time hydrogen ion excretion was also markedly elevated. Moreover, calcium excretion appeared to be associated with the phase of

_xenal regulation_dea!ing with the_dimination of previously stored-CD2. Urinary calcium excretion was elevated from the second to the fifth days of intermittent exposure to COs, in contrast to phosphorus, magnesium, hydroxyproline, and sulfur excretion, which did not show significant changes.

Blood bicarbonate increase is frequently used as a criterion of successful renal bicarbonate «absorption in response to C02 load. Inasmuch as blood bicarbonate did not increase during intermittent exposure to C02 (Fig. 4), the renal bicarbonate reabsorption mechanism apparently was not activated, which is in line with findings obtained in animal experiments during prolonged exposure to 1% C02 (Schaefer, Pasquale, Messier, and Niemoeller 1979).

The process of C02 elimination from C02 stores, which was shown by the increased alveolar and blood C02 tensions at the end of the nightly air-breathing period, did not involve renal regulation during the night. No change was observed in the pattern of urinary acid excretion during the night. This confirms previous findings of Carey, Schaefer, and Ciegg(1966), show- ing that C02 inhalation is not capable of altering the diurnal cycles of acid-base regulation or other diurnal cycles. During the first and third days of recovery on air after six days of intermittent exposure to C02, there was another increase in excretion of titratable acidity, organic acids, and ammonia. On the second day of recovery, between the increased levels of acid excretion, there was a strong bicarbonate diuresis, which is in agreement with post- exposure changes seen after prolonged exposure to 3% C02 (Glatte et al. 1967) and 1.5% C02

(Schaefer et al. 1964). Although this preliminary study was limited to one subject, it provided some new findings

about the limitation of ventilatory and renal responses to C02. The major results have been interpreted as follows:

1) The ventilatory response to C02 inhalation was not sufficient to prevent COj accumulation in the body.

2) The C02 accumulated in the body C02 stores was eliminated during the nightly air- breathing periods on the fourth and fifth days, as indicated by the higher blood and alveolar C02 values.

3) The renal response to C02 inhalation was stimulated during the first day of exposure, but not during the second and third days, and it was again triggered during the fourth and fifth days, when accumulated C02 was released from body C02 stores.

4) In contrast to the increased C02 elimination via the lungs that occurred during the air-breathing period at night, the renal elimination of C02 was not carried over into the air-breathing period at night.

5) The second renal response was associated with a marked increase in calcium excretion, which suggests that the bone C02 store was involved in the release of C02 since bone C02 and calcium exchange have been found to be intimately inter-connected (Schaefer et al. 1979).

The subject in this study was on a liquid diet with a known calcium and phosphorus content to ensure that electrolyte excretion, in particular that of calcium and phosphorus, and hydroxyproline excretion would not be influenced by changes in diet. Hydroxyproline excretion did not change from control levels throughout the whole experiment, indicating that bone resorption based on parathyroid stimulation was not involved in the calcium tide associated with the C02 release.

It should be mentioned that among the visual tests carried out during this experiment, night vision sensitivity and color sensitivity for green showed impairment repeatedly (Weitzman, Kinney, and Luria 1969).

I

INTERMITTENT EXPOSURE TO CQ, S133

Although this pilot experiment was limited to one subject, data obtained were of sufficient breadth to warrant a tentative definition of the effects of intermittent exposure to 3% C02 on several physiological systems. The observed findings reveal certain limitations of both the

-respiratory and-renal response-to-G02, which-were not know_nJfi_e_xist before now. New aspects of acid-base regulation through bone buffering during prolonged exposure to 0.8-1% C02 on submarine patrols are also reported in this supplement, and these aspects are related to the limitations of the respiratory and renal response to low levels of C02 (Schaefer 1979; Messier, Heyder, Braithwaite, McCluggage, Peck, and Schaefer 1979). The results of the experiment with intermittent exposure to 3% C02 can therefore serve as a model demon- strating the limitations of respiratory and renal regulation in response to C02 exposure.

) The subject, £. K., was a medical student enrolled in the Navy Clerkship Program. He had an excellent knowledge of | physiological functions, and developed a keen interest in the project. Only through his extraordinary motivation, practi-

cal skill in handling equipment, excellent cooperation, and patience was it possible to carry through a study that produced so many demands in the form of simultaneous physiological monitoring and actual performance. The support of Dr.

f Daniel Bernstein, Harvard School of Public Health, is gratefully acknowledged. Measurements of urinary calcium, i magnesium, phosphorus, sulfur, organic acids, and hydroxyproline as welt as fecal calcium, phosphorus, and magnesium i determinations were carried out in his laboratory.—Manuscript received for publication March 1978; revision received

August 1978. l

• Schaefer, K. E., C. R. Carey, J. H. Dougherty, Jr., C. Morgan, and A. A. Messier. 1979. Effets d'expositions intermittentes, ä 3% C02 sur la respiration, l'equilibre acido-basique, et le

f metabolisme du calcium et du phosphore. Undersea Biomed. Res. Sub. Suppl.; S115-S134.—Un i sujet a ete expose pendant 6 jours ä COj dont la concentration est augmentee de 0,03% jusqu'ä i 3,0% dans une periode de quinze heures. L'exposition a ete suivie de 9 heures en air. Pour evaluer ; l'equilibre acido-basique, du sang capillaire "arterialise" est preleve au doigt ä 8 h et ä 23 h

(commencement et fin de ia periode d'exposition). Des echantillons de sang veneux sont preleves aux memes heures d'autres jours. Les echantillons d'urine sont preleves deux fois. par jour. Le

I sujet resoit un diete de liquides. Les determinations de volume respiratoire minute au repos (VE), la | consommation d'oxygene (Voj), les pressions alveolaires de COj et de Oj (PACQ, et PAO,), et de j l'elimination de dioxyde de carbone (Vcoä) sont effectues deux fois par jour. Les pressions al- , veolaires sont contrölees aussi ä la fin des exercises d'apnee deux fois par jour. Des tests de

tolerance de CO, et du fonctionnement pulmonaire sont effectues aussi. Les tests de tolerance a ' COj traduisent une sensibilite accrue et PACO, inchange; on peut en conclure que l'acclimatation ä i COj n'a pas eu lieu. La reponse ventilatoire ä C02 ne suffit pas pour empecher Paccumulation de i COj corporel, accumulation eliminee au cours des periodes de respiration de l'air le 4e et 5e jour, ; comme le demontrent les valeurs accrues de PACO, et de Paco,. L* reponse renale ä l'hypercapnie

(elimination plus rapide de l'aciditä, de l'ammoniac, et des ions d'hydrogene) est observee; eile ! disparait apres le premier jour, pour reapparaitre le 4e et 5e jours, quand le CO, accumule a ete i libere. Cette seconde reponse renale est associee ä une elimination importante de calcium, ce qui i fait penser que les depots osseux de CQj y aient joue un role. ! I dioxyde de carbone fonction renale ! respiration metabolisme du calcium ; apnee

1

j REFERENCES

! Brackett, N. C, Jr., C. F. Wingo, O. Muren, and J. T. Salano. 1969. Acid-base response to chronic j hypercapnia in man. N. Engl. J. Med. 280: 124-130.

Bray's Clinical Laboratory Methods. 1962. Sixth ed. C. V. Mosby Co., p. 73. j Carey, C. R., K. E. Schaefer, and B. R. Clegg. 1966. Effect of chronic hypercapnia on circadian cycles. [ Aerosp. Med. 37: 268 (Abstract).

Chapin, J. L., A. B. Otis, and H. Rahn. 1956. Changes in the sensitivity of the respiratory center in man after prolonged exposure to 3% CO2. Wright Air Development Center Technical Rep. 55-357,250-254.

Clark, J. M., R. D. Sinclair, and B. E. Welch. 1971. Rate of acclimatization to chronic hypercapnia in man. Pages 399-408, in C. J. Lambertsen, Ed. Underwater physiology. Proceedings of the fourth symposium on underwater physiology. Academic Press, N.Y.


Fiske, Ci and Y. Subbarow. 1925. The colorimetric determination of phosphorus. J. Biol. Chem. 66- 375-400.

Gambino, S. R. 1959. Comparisons of pH in human arterial, venous, and capillary blood. Am. J. Clin Pathol. 32: 298-304. ____ ... , -1

Glatte, H. X., Jr., G. J. Motsay, and B. E. Welch. 1967. Carbon dioxide tolerance studies. USAF School of Aerospace Medicine, Aerospace Medical Division (AFSC). Brooks AFB, Texas. Rep. SMA-TR- 67-77.

Messier, A. A., E. Heyder, W. R. Braithwaite, C. McCIuggage, A. Peck, and K. E. Schaefer. 1979. Calcium, magnesium, and phosphorus metabolism, and parathyroid-calcitonin function during prolonged exposure to elevated C08 concentrations on submarines. Undersea Biomed. Res. Sub. Suppl. S57-S70:

Rahn, H., and W. O. Fenn. 1955. A graphical analysis of the respiratory gas exchange: the C02 - 02 diagram. , in Handbook of Physiology. Respiration. Bethesda: American Physiological Soci- ety.

Schaefer, K. E. 1949. Respiratory and acid-base balance during prolonged exposure to 3% CO* atmosphere. Pfliigers Archiv, gesamte Physiol. 251: 689-715.

Schaefer, K. E. 1961. A concept of triple tolerance limits based on chronic carbon dioxide toxicity studies. Aerosp. Med. 32: 197-204.

Schaefer, K. E., B. J. Hastings, C. R. Carey, and G. Nichols, Jr. 1963. Respiratory acclimatization to carbon dioxide. J. Appl. Physiol. 18(6): 1071-1078.

Schaefer, K. £., G. Nichols, Jr., and C. R. Carey. 1964. Acid-base balance and blood and urine electro- lytes of man during acclimatization to carbon dioxide. J. Appl. Physiol. 19(1): 48-58.

Schaefer, K. E., S. J. Pasquale, A. A. Messier, and H. Niemoeller. 1979. COj induced kidney calcifica- tion. Undersea Biomed. Res. Sub. Suppl. S143-S153.

Schaefer, K. E. 1979. Physiological stresses related to hypercapnia during patrols on submarines. Under- sea Biomed, Res. Sub. Suppl. S15-S47.

Schwartz, W. B., N. C. Brackett, and J. J. Cohen. 1965. The response of extracellular hydrogen ion concentration of graded degrees of chronic hypercapnia. The physiological limits of the defense of the pH. J. Clin. Invest. 44: 291-298.

Sullivan, W. J., and P. J. Dorman. 1955. Renal response to chronic respiratory acidosis. J. Clin. Invest. 34: 268-277.

Weitzman, D. O., J. A. S. Kinney, and S. M. Luria. 1969. Effect of vision on repeated exposure to carbon dioxide. Naval Submarine Medical Research Laboratory Rep. No. 566.

van Ypersele de Strihou, C, L. Brasseur, and J. DeConincok. 1966. The carbon dioxide response curve for chronic hypercapnia in man. N. Engl. J. Med. 275: 117-122.

Effect of intermittent exposure to 3% C0 respiration, …i !! / ' e? Undersea Biomedicat Research,...

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